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Biodegradable micelles self-assembled from miktoarm star block copolymers for MTX delivery

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Abstract

Biodegradable micelles based on disulfide-linked monomethoxy poly(ethylene glycol)-b-poly(methyl methacrylate)2 (mPEG-SS-PMMA2) miktoarm star block copolymers were synthesized through atom transfer radical polymerization procedure and applied to solubilization and delivery of methotrexate (MTX). The synthesized miktoarm star block copolymers were characterized by 1H nuclear magnetic resonance, Fourier transform infrared spectra, and gel permeation chromatography. The block copolymers were able to self-assemble into spherical micelles in water with an average diameter up to 130 nm by transmission electron microscopy observation and dynamic light scattering measurements and have a critical micelle concentration of 0.91 mg/L. When MTX was incorporated into obtained micelles, high drug loading capacity was found attributed to the designed miktoarm star-shaped nanostructure. Interestingly, in presence of dithiothreitol, the micelles could be degraded into polymer chains by cleavage of the disulfide linkages. The in vitro release studies revealed that these micelles released over 95 % of MTX within 48 h under a reductive environment analogous to that of the cell comparing to minimal drug release (<22 %) under nonreductive conditions. Cell cytoxicity experiments showed that the obtained micelles exhibited nontoxic, and the drug-loaded micelles exhibited high anticancer efficacy and better biocompatibility as compared to free MTX. All of these results showed that mPEG-SS-PMMA2 micelles are promising carriers for delivery of hydrophobic antitumor drugs.

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References

  1. Scarano W, Duong HTT, Lu H, De Souza PL, Stenzel MH (2013) Folate conjugation to polymeric micelles via boronic acid ester to deliver platinum drugs to ovarian cancer cell lines. Biomacromolecules 14:962–975

    Article  CAS  Google Scholar 

  2. Liu J, Pang Y, Huang W, Huang X, Meng L, Zhu X, Zhou Y, Yan D (2011) Bioreducible micelles self-assembled from amphiphilic hyperbranched multiarm copolymer for glutathione-mediated intracellular drug delivery. Biomacromolecules 12:1567–1577

    Article  CAS  Google Scholar 

  3. Laouini A, Koutroumanis KP, Charcosset C, Georgiadou S, Fessi H, Holdich RG, Vladisavljević GT (2013) pH-Sensitive micelles for targeted drug delivery prepared using a novel membrane contactor method. ACS Appl Mater Inter 5:8939–8947

    Article  CAS  Google Scholar 

  4. Zhou Q, Lin J, Wang J, Li F, Tang F, Zhao X (2009) A designed amphiphilic peptide containing the silk fibroin motif as a potential carrier of hydrophobic drugs. Prog Nat Sci 19:1529–1536

    Article  CAS  Google Scholar 

  5. Jin X, Mo R, Ding Y, Zheng W, Zhang C (2014) Paclitaxel-loaded n-octyl-o-sulfate chitosan micelles for superior cancer therapeutic efficacy and overcoming drug resistance. Mol Pharm 11:145–157

    Article  CAS  Google Scholar 

  6. Zhang L, Eisenberg A (1995) Multiple morphologies of “Crew-Cut” aggregates of polystyrene-b-poly (acrylic acid) block copolymers. Science 268:1728–1731

    Article  CAS  Google Scholar 

  7. Zhang L, Yu K, Eisenberg A (1996) Ion-induced morphological changes in “Crew-Cut” aggregates of amphiphilic block copolymers. Science 272:1777–1779

    Article  CAS  Google Scholar 

  8. Torchilin VP (2006) Multifunctional nanocarriers. Adv Drug Delivery Rev 58:1532–1555

    Article  CAS  Google Scholar 

  9. Kwon GS, Kataoka K (1995) Block copolymer micelles as long-circulating drug vehicles. Drug Delivery Rev 16:295–309

    Article  CAS  Google Scholar 

  10. Kataoka K, Harada A, Nagasaki Y (2001) Block copolymer micelles for drug delivery: design, characterization and biological significance. Adv Drug Delivery Rev 47:113–131

    Article  CAS  Google Scholar 

  11. Lin J, Luo J-B, Yang S-T, Zhou Q-H (2013) Template-directed self-assembly of a designed amphiphilic hexapeptide on mica surface. Colloid Polym Sci 291:2263–2270

    Article  CAS  Google Scholar 

  12. Yang J, Yan J, Zhou Z, Amsden BG (2014) Dithiol-PEG-PDLLA micelles: preparation and evaluation as potential topical ocular delivery vehicle. Biomacromolecules 15:1346–1354

    Article  CAS  Google Scholar 

  13. Ma R, Yang H, Li Z, Liu G, Sun X, Liu X, An Y, Shi L (2012) Phenylboronic acid-based complex micelles with enhanced glucose-responsiveness at physiological ph by complexation with glycopolymer. Biomacromolecules 13:3409–3417

    Article  CAS  Google Scholar 

  14. Wang F, Bronich TK, Kabanov AV, Rauh RD, Roovers J (2005) Synthesis and evaluation of a star amphiphilic block copolymer from poly (ε-caprolactone) and poly (ethylene glycol) as a potential drug delivery carrier. Bioconjugate Chem 16:397–405

    Article  CAS  Google Scholar 

  15. Wang F, Bronich TK, Kabanov AV, Rauh RD, Roovers J (2008) Synthesis and characterization of star poly (ε-caprolactone)-b-poly (ethylene glycol) and poly (l-lactide)-b-poly (ethylene glycol) copolymers: evaluation as drug delivery carriers. Bioconjugate Chem 19:1423–1429

    Article  CAS  Google Scholar 

  16. Pavlov GM, Knop K, Okatova OV, Schubert US (2013) Star-brush-shaped macromolecules: peculiar properties in dilute solution. Macromolecules 46:8671–8679

    Article  CAS  Google Scholar 

  17. Rao J, Zhang Y, Zhang J, Liu S (2008) Facile preparation of well-defined AB2 Y-shaped miktoarm star polypeptide copolymer via the combination of ring-opening polymerization and click chemistry. Biomacromolecules 9:2586–2593

    Article  CAS  Google Scholar 

  18. Cao W, Zhou J, Mann A, Wang Y, Zhu L (2011) Folate-functionalized unimolecular micelles based on a degradable amphiphilic dendrimer-like star polymer for cancer cell-targeted drug delivery. Biomacromolecules 12:2697–2707

    Article  CAS  Google Scholar 

  19. Poree DE, Giles MD, Lawson LB, He J, Grayson SM (2011) Synthesis of amphiphilic star block copolymers and their evaluation as transdermal carriers. Biomacromolecules 12:898–906

    Article  CAS  Google Scholar 

  20. Ni C, Wu G, Zhu C, Yao B (2010) The Preparation and characterization of amphiphilic star block copolymer nano micelles using silsesquioxane as the core. J Phys Chem C 114:13471–13476

    Article  CAS  Google Scholar 

  21. Lin J, Zhou Q-H, L-d L, Li Z-N (2014) Synthesis and self-assembly in bulk of star-shaped block copolymers based on helical polypeptides. Colloid Polym Sci 292:3177–3185

    Article  CAS  Google Scholar 

  22. Junnila S, Houbenov N, Karatzas A, Hadjichristidis N, Hirao A, Iatrou H, Ikkala O (2012) Side-chain-controlled self-assembly of polystyrene–polypeptide miktoarm star copolymers. Macromolecules 45:2850–2856

    Article  CAS  Google Scholar 

  23. Ostermann J, Merkl J-P, Flessau S, Wolter C, Kornowksi A, Schmidtke C, Pietsch A, Kloust H, Feld A, Weller H (2013) Controlling the physical and biological properties of highly fluorescent aqueous quantum dots using block copolymers of different size and shape. ACS Nano 7:9156–9167

    Article  CAS  Google Scholar 

  24. Ye C, Zhao G, Zhang M, Du J, Zhao Y (2012) Precise synthesis of ABCDE star quintopolymers by combination of controlled polymerization and azide–alkyne cycloaddition reaction. Macromolecules 45:7429–7439

    Article  CAS  Google Scholar 

  25. Liu H, Li S, Zhang M, Shao W, Zhao Y (2012) Facile synthesis of ABCDE-type H-shaped quintopolymers by combination of ATRP, ROP, and click chemistry and their potential applications as drug carriers. J Polym Sci A-Polym Chem 50:4705–4716

    Article  CAS  Google Scholar 

  26. McRae Page S, Martorella M, Parelkar S, Kosif I, Emrick T (2013) Disulfide cross-linked phosphorylcholine micelles for triggered release of camptothecin. Mol Pharm 10:2684–2692

    Article  CAS  Google Scholar 

  27. Sun H, Guo B, Cheng R, Meng F, Liu H, Zhong Z (2009) Biodegradable micelles with sheddable poly (ethylene glycol) shells for triggered intracellular release of doxorubicin. Biomaterials 30:6358–6366

    Article  CAS  Google Scholar 

  28. Sun Y, Huang Y, Bian S, Liang J, Fan Y, Zhang X (2013) Reduction-degradable PEG-b–PAA-b–PEG triblock copolymer micelles incorporated with MTX for cancer chemotherapy. Colloids Surf B 112:197–203

    Article  CAS  Google Scholar 

  29. Zhang Y, Jin T, Zhuo R-X (2005) Methotrexate-loaded biodegradable polymeric micelles: preparation, physicochemical properties and in vitro drug release. Colloids Surf B Biointerfaces 44:104–109

    Article  CAS  Google Scholar 

  30. Chassepot A, Gao L, Nguyen I, Dochter A, Fioretti F, Menu P, Kerdjoudj H, Baehr C, Schaaf P, Voegel J-C (2012) Chemically detachable polyelectrolyte multilayer platform for cell sheet engineering. Chem Mater 24:930–937

    Article  CAS  Google Scholar 

  31. Sui X, Zhang Z, Guan S, Xu Y, Li C, Lv Y, Chen A, Yang L, Gao L (2015) A facile strategy for the synthesis of block copolymers bearing an acid-cleavable junction. Polym Chem 6:2777–2782

    Article  CAS  Google Scholar 

  32. Jäger M, Wilke A (2003) Comprehensive biocompatibility testing of a new PMMA-HA bone cement versus conventional PMMA cement in vitro. J Biomater Sci Polymer Edn 14:1283–1298

    Article  Google Scholar 

  33. Ding X, Liu Y, Li J, Luo Z, Hu Y, Zhang B, Liu J, Zhou J, Cai K (2014) Hydrazone-bearing PMMA-functionalized magnetic nanocubes as pH-responsive drug carriers for remotely targeted cancer therapy in vitro and in vivo. ACS Appl Mater Interfaces 6:7395–7407

    Article  CAS  Google Scholar 

  34. Streubel A, Siepmann J, Bodmeier R (2003) Multiple unit gastroretentive drug delivery systems: a new preparation method for low density microparticles. J Microencapsul 20:329–347

    Article  CAS  Google Scholar 

  35. Sparnacci K, Laus M, Tondelli L, Bernardi C, Magnani L, Corticelli F, Marchisio M, Ensoli B, Castaldello A, Caputo A (2005) Core–shell microspheres by dispersion polymerization as promising delivery systems for proteins. J Biomater Sci Polym Ed 16:1557–1574

    Article  CAS  Google Scholar 

  36. Zhou Q-H, Zheng J-K, Shen Z, Fan X-H, Chen X-F, Zhou Q-F (2010) Synthesis and hierarchical self-assembly of rod-rod block copolymers via click chemistry between mesogen-jacketed liquid crystalline polymers and helical polypeptides. Macromolecules 43:5637–5646

    Article  CAS  Google Scholar 

  37. Matyjaszewski K, Miller PJ, Pyun J, Kickelbick G, Diamanti S (1999) Synthesis and characterization of star polymers with varying arm number, length, and composition from organic and hybrid inorganic/organic multifunctional initiators. Macromolecules 32:6526–6535

    Article  CAS  Google Scholar 

  38. Hanson JA, Li Z, Deming TJ (2010) Nonionic block copolypeptide micelles containing a hydrophobic rac-leucine core. Macromolecules 43:6268–6269

    Article  CAS  Google Scholar 

  39. Ren T-B, Xia W-J, Dong H-Q, Li Y-Y (2011) Sheddable micelles based on disulfide-linked hybrid PEG-polypeptide copolymer for intracellular drug delivery. Polymer 52:3580–3586

    Article  CAS  Google Scholar 

  40. Hu Y, Zhang L, Cao Y, Ge H, Jiang X, Yang C (2004) Degradation behavior of poly (ε-caprolactone)-b-poly (ethylene glycol)-b-poly (ε-caprolactone) micelles in aqueous solution. Biomacromolecules 5:1756–1762

    Article  CAS  Google Scholar 

  41. Kang H, Kim J-D, Han S-H, Chang I-S (2002) Self-aggregates of poly (2-hydroxyethyl aspartamide) copolymers loaded with methotrexate by physical and chemical entrapments. J Control Release 81:135–144

    Article  CAS  Google Scholar 

  42. Ashwanikumar N, Kumar NA, Nair SA, Kumar GSV (2014) Dual drug delivery of 5-fluorouracil (5-FU) and methotrexate (MTX) through random copolymeric nanomicelles of PLGA and polyethylenimine demonstrating enhanced cell uptake and cytotoxicity. Colloids Surf B Biointerfaces 122:520–528

    Article  CAS  Google Scholar 

  43. Baranello MP, Bauer L, Benoit DSW (2014) Poly (styrene-alt-maleic anhydride)-based diblock copolymer micelles exhibit versatile hydrophobic drug loading, drug-dependent release, and internalization by multidrug resistant ovarian cancer cells. Biomacromolecules 15:2629–2641

    CAS  Google Scholar 

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Acknowledgments

This work was financially supported by the National Natural Science Foundation of China (Grant Nos. 21404086) and the Project of Postgraduate Degree Construction, Southwest University for Nationalities (No. 2015XWD-S0703).

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Authors and Affiliations

  1. College of Chemical and Environment Protection, Southwest University for Nationalities, First Ring Road, 4th Section No.16, Chengdu, Sichuan, 610041, China

    Qing-Han Zhou, Li-Dong Li & Le Shang

  2. School of Biomedical Sciences, Chengdu Medical College, 601 Tianhui Road, Chengdu, Sichuan, 610083, China

    Juan Lin

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  1. Qing-Han Zhou
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Correspondence to Qing-Han Zhou or Juan Lin.

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Zhou, QH., Lin, J., Li, LD. et al. Biodegradable micelles self-assembled from miktoarm star block copolymers for MTX delivery. Colloid Polym Sci 293, 2291–2300 (2015). https://doi.org/10.1007/s00396-015-3610-z

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  • DOI: https://doi.org/10.1007/s00396-015-3610-z

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